Tuberculosis remains an important life-threatening disease and has recently been declared to be a global health emergency by the World Health Organization. While human CD4 T cells play a crucial role in immune protection against M. tuberculosis infection, other T cell populations are poorly characterized for their roles in immunity to tuberculosis. We have recently demonstrated that memory responses of mycobacterium-specific CDS T cells after M. tuberculosis infection coincided with protection against fatal tuberculosis in BCG-vaccinated monkeys, and that antibody-mediated depletion of CD8 T cells in monkeys with protective memory resulted in the development of severe forms of tuberculosis following M. tuberculosis re-infection by aerosol. Based on these results, we hypothesize that mycobacterium-specific CD8 T cells are an important component of immunity against tuberculosis. In testing this hypothesis, we will answer immune mechanistic questions involving CD8 T cell-mediated anti-tuberculosis immunity. We will: I. Determine the role of CD8 T cells in resistance to primary M. tuberculosis infection. II. Determine the role of CD8 T cells in adaptive immunity to M. tuberculosis re-infection and reactivation tuberculosis. A. Determine the role of CD8 T cells in adaptive immunity against M. tuberculosis re-infection. B. Determine the role of CD8 T cells in controlling reactivation tuberculosis in normal monkeys and SIVmac-infected macaques. III. Determine if vaccine-elicited CD8 T cell responses can confer some protection against tuberculosis in immune competent and SHIV-infected monkeys. A. Examine vaccine-elicited CD8 T cell responses and determine if such immune responses can confer some degree of protection against M. tuberculosis infection in normal monkeys. B. Determine if vaccine-elicited CD8 T cell responses can contribute to immune protection against tuberculosis in SHIV-89.6P-infected monkeys.